Treating fungal infections represents a profound medical challenge. For example, infections by the ubiquitous fungus Candida albicans, commonly referred to as yeast infections, can be either systemic or topical and are a persistent health problem in some patient populations. Topical infections, called candidiasis, can infect the mouth (“thrush”), vagina, skin, stomach, and urinary tract. Approximately seventy-five percent of women will get candidiasis of the vagina during their lifetime, and ninety percent of all people with HIV/AIDS develop Candida spp. infections. These infections, while typically not life threatening, produce numerous unpleasant side effects and are generally treated with topical antifungal ointments containing clotrimazole or with oral or intravenous medications containing fluconazole or amphotericin B, especially for systemic infections.
Systemic infections, referred to as candidemia and characterized by presence of the organism in the bloodstream, however, are a significant and often life-threatening clinical problem. These infections most commonly occur in the presence of an indwelling medical device (e.g., intravascular catheter) or in immunosuppressed patients. The vast majority of these infections are nosocomial (i.e. occur in the hospital in conjunction with treatment for a primary ailment). Candidemias are associated with significant attributable mortality and prolonged hospitalization. The present choice of antifungal is between azole drugs (most commonly fluconazole) and amphotericin B; the latter typically viewed as more effective but also extremely toxic.
Natural and synthetic small molecule antifungal agents are known, but their use as therapeutics is limited by their inherent toxicity to humans and increasing incidence of resistance. For example, amphotericin B was initially discovered in the 1950s. It causes cell death by inhibiting synthesis of ergosterol, a component of the fungal cell membrane. Amphotericin B must be administered intravenously and can only be given for a limited number of days without leading to kidney or vascular damage or both. Liposomal formulations and micellar formulations have been developed which result in lower toxicity; however these formulations are considerably more expensive than conventional amphotericin B formulations.
Host-defense peptides, components of the innate immune system that are very effective against prokaryotic pathogens, have been reported to display antifungal activity under some conditions in vitro, but the relevance of these results to in vivo activity is unclear. Hydrophobic appendages have been shown to enhance the antifungal activity of host-defense peptides and designed sequences.
Several researchers have explored unnatural oligomers composed of β-amino acids (“β-peptides”) as mimics of host-defense α-peptides in the antibacterial context. β-Peptide “foldamers” can be designed to adopt helical conformations that display discrete hydrophobic and cationic surfaces, thereby mimicking the globally amphiphilic α helical conformations of many host-defense peptides, including magainins and cecropins. Some β-peptides have been shown to display antibacterial activity comparable to that of the host-defense α-peptide prototypes. However, the use of β-peptides in the realm of combating fungal pathogens has received little, if any, attention.
As can be appreciated by the foregoing, a need exists for alternative antifungal agents, particularly agents that exhibit low toxicity to the subject.